Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma

Background: Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage. Therefore, eIF4F translation initiation complex components are attractive therapeutic targets. Methods: Protein lysates of myeloma cells (cell lines/patients' bone marrow samples) untreated/treated with bevacizumab were assayed for eIF4GI expression, regulation (NQO1/proteosome dependent fragmentation) (WB, Dicumarol, qPCR) and targets (WB). eIF4GI was inhibited by knockdown and 4EGI-1. Cells were tested for viability (ELISA), death (FACS) and eIF4GI targets (WB). Results: Previously, we have shown that manipulation of VEGF in myeloma cells attenuated eIF4E dependent translation initiation. Here we assessed the significance of eIF4GI to MM cells. We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon VEGF inhibition attributed to elevated NQO1/proteasome dependent fragmentation and diminished mRNA levels. Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets (SMAD5/ER alpha/HIF1 alpha/c-Myc). Finally, we showed that the small molecule 4EGI-1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma. Conclusion: Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI, critical to cell phenotype, and mark it as a viable target for pharmacological intervention. (C) 2014 Elsevier Inc. All rights reserved.